Interleukin-21 enhances NK cell activation in response to antibody-coated targets

Julie M. Roda, Robin Parihar, Amy Lehman, Aruna Mani, Susheela Tridandapani, William E. Carson

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99 Scopus citations

Abstract

NK cells express an activating FcR (FcγRIIIa) that mediates Ab-dependent cellular cytotoxicity and the production of immune modelatory cytokines in response to Ab-coated targets. IL-21 has antitumor activity in murine models that depends in part on its ability to promote NK cell cytotoxicity and IFN-γ secretion. We hypothesized that the NK cell response to FcR stimulation would be enhanced by the administration of IL-21. Human NK cells cultured with IL-21 and immobilized IgG or human breast cancer cells coated with a therapeutic mAb (trastuzumab) secreted large amounts of IFN-γ. Increased secretion of TNF-α and the chemokines IL-8, MIP-1α, and RANTES was also observed under these conditions. NK cell IFN-γ production was dependent on distinct signals mediated by the IL-21R and the FcR and was abrogated in STAT1-deficient NK cells. Supernatants derived from NK cells that had been stimulated with IL-21 and mAb-coated breast cancer cells were able to drive the migration of naive and activated T cells in an in vitro chemotaxis assay. IL-21 also enhanced NK cell lytic activity against Ab-coated tumor cells. Coadministration of IL-21 and Ab-coated tumor cells to immunocompetent mice led to synergistic production of IFN-γ by NK cells. Furthermore, the administration of IL-21 augmented the effects of an anti-HER2/neu mAb in a murine tumor model, an effect that required IFN-γ. These findings demonstrate that IL-21 significantly enhances the NK cell response to Ab-coated targets and suggest that IL-21 would be an effective adjuvant to administer in combination with therapeutic mAbs.

Original languageEnglish (US)
Pages (from-to)120-129
Number of pages10
JournalJournal of Immunology
Volume177
Issue number1
DOIs
StatePublished - Jul 1 2006

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Roda, J. M., Parihar, R., Lehman, A., Mani, A., Tridandapani, S., & Carson, W. E. (2006). Interleukin-21 enhances NK cell activation in response to antibody-coated targets. Journal of Immunology, 177(1), 120-129. https://doi.org/10.4049/jimmunol.177.1.120